Contraception Research and Development

在一项新的研究中，德国亥姆霍兹慕尼黑中心的Marcus Conrad博士领导的一个研究团队发现了一种名为icFSP1的新型抗癌药物，它能使癌细胞对铁死亡（ferroptosis）敏感。相关研究结果于2023年6月28日在线发表在Nature期刊上，论文标题为“Phase separation of FSP1 promotes ferroptosis”。铁死亡的特点是细胞膜的铁依赖性氧化破坏，这种破坏可被铁死亡抑制蛋白-1（ferroptosis suppressor protein-1, FSP1）抵消。尽管FSP1被认为是癌症治疗的一种有吸引力的药物靶标，但一直缺乏体内有效的FSP1抑制剂。为此，在这项新的研究中，这些作者仔细评估了从大约10000种小分子化合物中筛选出的命中率，并确定icFSP1为一种新的体内有效药物。重要的是，他们发现了icFSP1的作用机制，该机制基于触发FSP1的相分离，其中相分离是细胞中类似于油和水分离的物理现象。事实上，icFSP1在体内强烈地抑制了肿瘤生长，肿瘤组织中有明显的FSP1凝聚物，从而提出了一种通过促进FSP1的相分离和铁死亡来对抗肿瘤的新概念。icFSP1是一种体内适用的FSP1抑制剂对化疗的抵抗性或癌症转移是癌症的一个重要临床问题。值得注意的是，在去分化或代谢重建的过程中，某些恶性肿瘤细胞获得了对铁死亡的内在脆弱性。因此，靶向铁死亡作为一种癌症治疗方法已经显示出巨大的前景。2019年，与Conrad合作的一个研究小组已确定了第一种FSP1特异性抑制剂，被称为iFSP1。Conrad解释说，“然而，这种化合物不适合在体内使用，而且在高浓度下会表现出脱靶效应。”为了确定靶向FSP1的体内活性铁死亡诱导剂，该团队在细胞中进行了筛选，随后进行了药物代谢与药代动力学（drug metabolism and pharmacokinetics, DMPK）验证研究。这些努力最终导致了icFSP1被确定为一类新型化合物，使许多人类癌症细胞对铁死亡敏感，并在体内减弱肿瘤生长。icFSP1触发了FSP1的相分离通过详细研究icFSP1的内在作用机制，该团队进一步发现icFSP1并不直接抑制FSP1酶的活性，而是在一种称为相分离（phase separation）的过程中触发了FSP1的亚细胞重定位。这些结果与第一种FSP1抑制剂---iFSP1---的作用机制相反。icFSP1与GPX4抑制协同诱导铁死亡。图片来自Nature, 2023, doi:10.1038/s41586-023-06255-6。论文第一作者Toshitaka Nakamura进一步解释说，“icFSP1诱导的FSP1凝聚需要不同的结构成分和N末端豆蔻酰化”，这一点通过使用重组的FSP1蛋白以及不同的细胞系和肿瘤样本得到了证明。突破：将铁死亡和相分离联系起来在癌症、神经退行性疾病和类似于相分离过程的缺血/再灌注损伤等许多领域，铁死亡引起了人们的极大兴趣，这是与多种疾病相关的信号转导和基础生物学的基本物理现象。这项研究首次揭示了铁死亡和相分离之间的联系。Conrad解释说，“因此，我们的研究将作为一种很好的模型，用于进一步开发某些疾病的创新治疗方法，包括癌症，在这些疾病中铁死亡/相分离起着重要的作用”，这就为未来提供了充满希望的前景。参考资料：1. Toshitaka Nakamura et al. Phase separation of FSP1 promotes ferroptosis. Nature, 2023, doi:10.1038/s41586-023-06255-6.2. New Approach in Cancer Therapy With Innovative Mechanism-of-Action for Ferroptosis Inductionhttps://www.helmholtz-munich.de/en/newsroom/news-all/artikel/new-approach-in-cancer-therapy-with-innovative-mechanism-of-action-for-ferroptosis-induction会议推荐1大会信息  会议名称 | 2023第六届单细胞多组学研究与临床应用峰会会议时间 | 2023年9月14-15日会议地点 | 上海虹桥西郊丽笙大酒店大会规模 | 800人主办单位 | 生物谷扫码立即报名

Senators Hillary Rodham Clinton (D-NY) and Patty Murray (D-Wash) on Thursday called for an investigation into whether a memo written by FDA adviser and conservative evangelical OB/GYN David Hager influenced the agency's decision not to approve... Barr Laboratories' application for nonprescription sales of the emergency contraceptive Plan B in May 2004, Reuters reports (Richwine, Reuters, 5/12). The agency issued a "not approvable" letter in response to Barr's original application, which would have allowed Plan B to be sold to any woman without a doctor's prescription. FDA's decision contradicted the recommendations of two agency advisory panels and cited inadequate data on the use of the pills among girls ages 16 and younger. Hager -- who was named an adviser to the FDA's reproductive drugs panel in 2002 -- during an October 2004 sermon in Wilmore, Ky., said that after the advisory panels voted to approve nonprescription sales of Plan B, he was asked to "write a minority opinion that was sent to the commissioner of the FDA." He added, "I argued it from a scientific perspective, and God took that information and he used it through this minority report to influence the decision." Hager continued, "For only the second time in five decades, the FDA did not abide by its advisory committee opinion, and the measure was rejected." Hager in an e-mail to the Washington Post said the request for the minority report came from "outside the agency," but he previously had told two other journalists that the request came from an FDA staff member. An unnamed FDA spokesperson said the agency did not ask Hager to write a report and that Hager sent a so-called "private citizen letter" to then FDA Commissioner Mark McClellan (Kaiser Daily Reproductive Health Report, 5/12).